Exposure of malignant thymocytes to glucococorticoids halts the proliferation of these cells. Cell death and cytolysis ensue. For this reason, glucocorticoids have been widely used in the treatment of malignant lymphoproliferative diseases such as leukemias and lymphomas. The efficacy of hormone treatment is diminished, however, by the fact that glucocorticoid-resistant populations of cells often emerge upon steroid treatment. We are investigating the mechanism whereby such cells arise in vivo. Cytolysis-resistant mouse thymic lymphosarcoma cells, selected in vivo, invariably contain presumptive glucocorticoid receptors equal in number to those observed in sensitive cells. The extent of nuclear translocation is the same in both sensitive and resistant cells. We propose to determine if these receptors are functional. Three approaches will be used; 1) activity of enzymes known to be regulated by glucocrticoids, 2) expression of the mouse mammary tumor proviral genome, and 3) somatic cell hybirds formed from resistant cells and receptor-negative cells selected from a sensitive background. In addition, we will compare the properties of resistant cells selected from cloned sensitive cells exposed to glucocorticoids in vivo and in culture. In this way, we will determine if the host influences the mechanism whereby cells acquire resistance to the cytolytic effects of flucocorticoids. Finally, we will study the properties of thymic eqithelial cells in culture. These will be characterized as potential target cells for estrogens and glucocorticoids. We will determine if epithelial cells can influence the rate of proliferation and/or glucocorticoid sensitivity of normal and malignant thymocytes. An understanding of the mechanisms whereby cells alter their responsiveness to steroid hormones is of critical importance in endocrinology and medicine. The studies outlined above are unique in the that they will elucidate the mechanisms which impinge on this process in vivo. The results will yield important information about the mechanism of action of steroid hormones as well as the usefulness of such steroids as chemotherapeutic agents.